This invention relates to an improved industrial process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof, in which the end product is obtained in a exceptionally pure form.
Several methods have been reported for preparation of .omega.-amino-1-hydroxyalkylidene-1,1-bisphosphonic acids in general and 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in particular. The syntheses basically consist of reacting the corresponding .omega.-amino acid with a mixture of phosphorous acid and one of the three phosphorus chlorides--phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride, then quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyse the phosphorous intermediates to the final product.
U.S. Pat. No. 4,407,761 (Blom et al.) to Henkel Kommanditgesellschaft teaches how to prepare also 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid beside other bisphosphonic acids. The reaction is carried out at about 100.degree. C. in chlorobenzene as a diluent which does not solubilize the reaction components and serves only as a heat carrier. The reaction starts as a two phase system, in which the melt gradually thickens into a non-stirrable mass. This semisolid sticky mass finally turns into a hard, rigid material coated on the walls of the reaction vessel which is preventing smooth heat transfer. The process might be suitable for laboratory preparation of gram quantities of the product, however, for industrial production it is not acceptable and is not reasonable even for a modest scaleup.
The above described flaws of the process were acknowledged by Kieczykowski et al., who in Application For Canadian Patent 2,018,477 and 2,044,923 to Merck & Co. revealed a solution to the solidification problem. Methanesulfonic acid was used to solubilize the reaction components and keep it fluid up to completion of the reaction. Although the problems with physical characteristics of the reaction were solved, a safety problem surfaced. Methanesulfonic acid reacts with phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85.degree. C. and an uncontrolled exotherm occurs at &gt;140.degree. C. This fact was recognized by the authors of the invention and in Example 1 of both Applications For Canadian Patent (2,018,477 and 2,044,923) caution is raised. The safety concern in somewhat more detail is mentioned by the authors (Kieczykowski et al.) in an article of J. Org. Chem. 1995, 60, 8310-8312.
The present invention solves both, the solidification and the safety problems by the use of a poly(alkylene glycol) or its derivative. Poly(alkylene glycols) solubilize the reaction components and do not react with the reactants to cause any uncontrolled reactions. The process is suitable for commercial manufacturing and can be scaled to large vessels with no danger of temperature escalation. The reaction can be carried out also at elevated temperatures. Since polyalkylene glycols and its derivatives are soluble in water, the reaction mixture can be quenched into water, the intermediates subsequently hydrolysed and the final product directly isolated.